The pathogenesis of obesity in man remains undetermined although there are likely to be genetic and environmental components. The purpose of this study is to identify factors that may be responsible for adipocyte recruitment or hypertrophy and to correlate the presence of these factors with changes in energy metabolism. We hypothesize that individuals who are resistant to weight gain lack the ability to recruit adipocytes and/or initiate adipocyte hypertrophy because of altered adipocyte gene expression and thereby employ alternative metabolic pathways to expand energy. Sixteen subjects were overfed by 1000 kcal/day in excess of weight maintenance requirements. Changes in resting energy expenditure and thermic effect of food could not account for the changes in fat gain. Increases in non-exercise activity thermogenesis (NEAT) accounted for two thirds of the increases in total daily expenditure, were sufficiently diverse to explain the ten-fold range in fat storage we detected and directly predicted resistance to fat gain with over-feeding. We concluded that as humans over-eat, activation of non-exercise activity thermogenesis can result in dissipation of excess energy to preserve leanness and that failure to active NEAT resulted in ready fat gain and predisposition to obesity.